EP1399176B1 - Antibiotiques glycopeptidiques sensiblement purs ac-98-1; ac-98-2; ac-98-3; ac-98-4 et ac-98-5 - Google Patents

Antibiotiques glycopeptidiques sensiblement purs ac-98-1; ac-98-2; ac-98-3; ac-98-4 et ac-98-5 Download PDF

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EP1399176B1
EP1399176B1 EP02739179A EP02739179A EP1399176B1 EP 1399176 B1 EP1399176 B1 EP 1399176B1 EP 02739179 A EP02739179 A EP 02739179A EP 02739179 A EP02739179 A EP 02739179A EP 1399176 B1 EP1399176 B1 EP 1399176B1
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substantially pure
antibiotics
mixture
glycopeptide antibiotics
magnetic resonance
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EP1399176A1 (fr
EP1399176A4 (fr
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Guy Thomas Carter
Haiyin He
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Wyeth Holdings LLC
Wyeth LLC
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Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to new substantially pure glycopeptide antibiotics, designated AC-98-3, AC-98-4 and AC-98-5, or pharmaceutically acceptable salts thereof, to methods for the preparation and isolation of such antibiotics, to methods of utilizing such antibiotics to treat bacterial infections and to pharmaceutical compositions containing such antibiotics.
  • U.S. Pat. No. 3,495,004 discloses a producing organism Streptomyces hygroscopicus NRRL 3085, and production conditions to prepare a complex mixture of antibiotics AC-98. No details of the structures of the individual antibiotics are disclosed. As described in U.S. Patent 3,495,004 , the mixture of AC98 antibiotics could not be separated into single components by ion exchange (IRC-50), gel filtration (CM-sephadex), or normal phase chromatography (deactivated silica gel).
  • IRC-50 ion exchange
  • CM-sephadex gel filtration
  • normal phase chromatography deactivated silica gel
  • AC-98-1 The structure of AC-98-1 is:
  • AC-98-1 The physico chemical characteristics of AC-98-1 are as follows:
  • AC-98-2 The structure of AC-98-2 is:
  • AC-98-2 The physico chemical characteristics of AC-98-2 are as follows:
  • AC-98-3 The structure of AC-98-3 is:
  • AC-98-3 The physico chemical characteristics of AC-98-3 are as follows:
  • AC-98-4 The structure of AC-98-4 is:
  • AC-98-4 The physico chemical characteristics of AC-98-4 are as follows:
  • AC-98-5 The structure of AC-98-5 is:
  • AC-98-5 The physico chemical characteristics of AC-98-5 are as follows:
  • This invention provides a method of preparing, separating and isolating substantially pure glycopeptide antibiotics AC-98-3, AC-98-4, and AC-98-5 from a recovered complex mixture.
  • a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • This invention further provides a method for preparing substantially pure glycopeptide antibiotic AC-98-3 comprising the steps of:
  • a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • This invention further provides a method for preparing substantially pure glycopeptide antibiotic AC-98-4 comprising the steps of:
  • a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • This invention further provides a method for preparing substantially pure glycopeptide antibiotic AC-98-5 comprising the steps of:
  • a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • substantially pure antibiotics AC-98-3, AC-98-4 and AC-98-5 may be obtained as pharmaceutically acceptable salts which are those derived from such organic and inorganic acids as: acetic, trifluoroacetic, lactic, citric, tartaric, formate, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • the pharmaceutically acceptable salts of compounds of the invention are prepared using conventional procedures.
  • Substantially pure compounds of the invention have centers of asymmetry.
  • the substantially pure compounds may, therefore, exist in at least two and often more stereoisomeric forms.
  • the present invention encompasses all stereoisomers of the substantially pure compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixtures of enantiomers as well as the diastereomeric mixtures of isomers.
  • the absolute configuration of any substantially pure compound may be determined by any suitable method including conventional X-ray crystallography.
  • the present invention accordingly provides a pharmaceutical composition which comprises a substantially pure glycopeptide antibiotic AC-98-3, AC-98-4 or AC-98-5 or a mixture thereof in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of substantially pure AC-98-3, AC-98-4 or AC-98-5 or a mixture thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides medicaments for use in treating bacterial infections in warm blooded animals which comprise administering to said animals an antibacterially effective amount of a substantially pure AC-98-3, AC-98-4 or AC-98-5 or a mixture thereof.
  • Warm blooded animals includes humans.
  • New substantially pure glycopeptide antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4 and AC-98-5 are obtained from a complex AC-98 antibiotic mixture which is produced by aerobic fermentation of the culture ( Streptomyces hygroscopicus ) NRRL 3085 using the conditions as described in U.S. Pat. No. 3,495,004 .
  • This culture is maintained in the culture collection of Wyeth-Ayerst Research, Pearl River, NY as culture number AC-98.
  • a viable culture of this microorganism has been deposited, with the ARS Culture Collection, Fermentation Laboratory, Northern Regional Research Center, U.S.
  • NRRL 3085 Another suitable producing strain of Streptomyces hygroscopicus is NRRL 4600 (NRRL30439).
  • the HPLC is performed with C18 reverse phase columns (YMC ODS-A, 120A pore size) using mixtures of acetonitrile or methanol in water containing small amounts of trifluoroacetic acid to control the acidity in the range of pH 3.5 and 5.5.
  • the purification of the substantially pure antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 from the AC-98 antibiotic mixture is finally achieved by dissolving the AC-98 mixture in water or water/methanol mixture and subjecting the resulting solution to reverse phase HPLC.
  • Separating the substantially pure AC-98-1, AC-98-2, AC-98-3, AC-98-4 or AC-98-5 each from the others is accomplished using reverse phase HPLC on a C18 column (YMC ODS-A, 8 ⁇ m particle size, 20 X 250 mm) using a mobile phase consisting of a gradient from about 11 % to about 25% by volume of acetonitrile in water containing about 0.02% trifluoroacetic.
  • the flow rate of the mobile phase is maintained constant at 9 ml/minute and the effluent monitored by UV absorbance at 226 nm.
  • Substantially pure AC-98-5 is further separated using reverse phase HPLC and a mobile phase gradient of about 40% to about 60% methanol in water containing about 0.02% trifluoroacetic acid.
  • Substantially pure glycopeptide antibiotics AC-98-3, AC-98-4 and AC-98-5 of this invention are defined as having, a purity of at least 85% when separated each from the others, as determined by high pressure liquid chromatography(HPLC).
  • substantially pure AC-98-1 is obtained with a purity of at least 92%
  • substantially pure AC-98-2 is obtained with a purity of at least 94%
  • substantially pure AC-98-3 is obtained with a purity of at least 89%
  • substantially pure AC-98-4 is obtained with a purity of at least 91 %
  • substantially pure AC-98-5 is obtained with a purity of at least 89%.
  • the substantially pure glycopeptide antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 are isolated, purified and characterized from the AC-98 antibiotic mixture by dissolving the mixture in water or a water/methanol mixture and subjecting the resulting solution to reverse phase chromatography.
  • the chromatography is performed with C18 reverse phase media using mixtures of acetonitrile or methanol in water containing small amounts of organic acids, such as trifluoroacetic acid to control the acidity in the range of pH 3.5 and 5.5.
  • Cultivation of suitable producing strains of Streptomyces hygroscopicus may be carried out in a wide variety of suitable liquid culture media.
  • Media which are useful for the production of AC-98 glycopeptide antibiotics include an assimilable source of carbon, such as dextrin, dextrose, sucrose, molasses, starch, glycerol, etc; an assimilable source of nitrogen such as protein, protein hydrolysate, polypeptides, amino acids, corn steep liquor, etc; and inorganic anions and cations, such as potassium, sodium, ammonium, calcium, sulfate, carbonate, phosphate, chloride, etc.
  • an assimilable source of carbon such as dextrin, dextrose, sucrose, molasses, starch, glycerol, etc
  • an assimilable source of nitrogen such as protein, protein hydrolysate, polypeptides, amino acids, corn steep liquor, etc
  • Trace elements such as zinc, cobalt, iron, boron, molybdenum, copper, etc., are supplied as impurities of other constituents of the media. Aerobic conditions include aeration in tanks and bottles supplied by forcing sterile air through or onto the surface of the fermenting medium. Further agitation in tanks is provided by a mechanical impeller. An antifoam agent such as polypropylene glycol may be added as needed.
  • cultivating a suitable producing strain of Streptomyces hygroscopicus in a suitable culture medium is continued for about 24 to about 240 hours to produce a mixture of AC-98 antibiotics containing AC-98-1, AC-98-2, AC-98-3, AC-98-4 and AC-98-5.
  • suitable liquid culture media are listed in Table A.
  • Cultures may be preserved as frozen whole cells (frozen vegetative mycelia, FVM) at -70°C.
  • Glycerol may be added to cells grown for 24-48 hours in TSBG (Tryptic soy broth [Difco] supplemented with 20 g/L glucose) to a final concentration of 20%. The suspension may then be aliquoted to cryovials and frozen.
  • Fermentations may be inoculated from "seed" stage cells grown in TSBG medium.
  • Inoculum cells may be grown in various configurations depending on the fermentation scale, such as in test tubes containing 10 ml medium, shake-flasks containing 25, 50, 250 or 500 ml medium or in 10-liter fermentor.
  • Primary seeds (tube, flask) may be inoculated from FVM at 0.2-5.0% and incubated on rotary shaker at 30°C for 24-48 hours. Primary seeds may be used for inoculation of shake-flask and ten-liter fermentors.
  • a second stage, ten-liter TSBG seed fermentor may be used for inoculation of 300-liter fermentations.
  • Seed fermentors may be operated at 30°C, 500 rpm with 1 wm air for 24-48 hours.
  • Table A Composition of fermentation media Component BPM17 BPM17stat BPM17st atgal BPM17st atman BPM27 BPM27 -man Pharmame dia (Traders) 10 g/L 20 g/L 20 g/L 20 g/L 20 g/L 20 g/L Glucose 40 g/L 60 g/L 60 g/L 60 g/L 60 g/L 60 g/L 60 g/L Galactose - - 20 g/L - - - Mannose - - - 2 g/L 2 g/L - CaCO 3 (Mississippi Lime) 5 g/L 5 g/L 5 g/L 5 g/L 5 g/L - - CaCO 3 (Gamaco) - - - - 15 g/L 15
  • Shake-flask fermentations may be performed at 30°C on a gyro-rotary shaker operating at 250 rpm (2" stroke) for from 3- 5 days.
  • Ten-liter fermentations may be performed at 30°C for 3-5 days at 30°C, at 400-800 rpm with1 vvm airflow.
  • Fermentation at 300 liters may be performed similarly with agitation at 170-200 rpm.
  • a polypropylene glycol antifoam, such as Macol P2000 may be added to fermentor medium at 0.2-2.0%.
  • Three hundred-liter fermentations with medium BPM17statgal employ galactose at 8 g/L rather than the smaller scale concentration of 20 g/L.
  • the molecular weights of new substantially pure AC-98 glycopeptide antibiotics may be determined using a Hewlett-Packard API-electrospray LC/MS system with an HP 5989B Mass Spectrometer, HP 59987A API-Electrospray, HP 1090 series II HPLC and HP ChemStation data system with HP G1047A LC/MS software and UV detection at 226 nm.
  • the MS electrospray may be performed in positive mode with a scan range of 400 ⁇ 1700 m/z.
  • glycopeptide antibiotics of the AC-98 complex may be isolated from fermentations by passing supernatant through a column containing methacrylate resin XAD-7.
  • the mixture of glycopeptide antibiotics of the AC-98 complex retained on the column may then be eluted by a mixed solvent of acetonitrile in water containing a small amount of acid.
  • the individual compounds may be purified by reverse phase chromatography.
  • the chromatography is performed with C18 reverse phase media using mixtures of acetonitrile or methanol in water with small amount of acid for pH control, the preferred acid being trifluoroacetic acid.
  • Substantially pure glycopeptide antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 derive their utility from their antibacterial activity.
  • the substantially pure antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4 and AC-98-5 are active against methicillin-susceptible and methicillin-resistant strains of staphylococci, against penicillin-susceptible and penicillin-resistant streptococci, and against vancomycin-susceptible and vancomycin-resistant enterococci.
  • these compounds may be used in the suppression of bacterial infections, as a topical antibacterial agent and as a general disinfectant for laboratories.
  • the substantially pure glycopeptide antibiotics AC-98-3, AC-98-4, and AC-98-5 of this invention may be administered in the form of conventional pharmaceutical compositions appropriate for the intended use. Such compositions may be formulated so as to be suitable for oral, parenteral or topical administration.
  • the substantially pure glycopeptide antibiotics AC-98-3, AC-98-4, and AC-98-5 may be combined in admixture with a nontoxic pharmaceutical carrier, which carrier may take a variety of forms, depending on the form of preparation desired for administration, ie. oral, parenteral, or topical.
  • substantially pure glycopeptide antibiotics AC-98-3, AC-98-4, and AC-98-5 are employed for the above utility, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example from about 10 to 50% of sugar, and elixirs containing, for example from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the substantially pure glycopeptide antibiotics AC-98-3, AC-98-4, and AC-98-5 in combination with the carrier, more usually between about 5% and 60% by weight.
  • An antibacterially effective amount of substantially pure glycopeptide antibiotics AC-98-3, AC-98-4 or AC-98-5 from about 0.5 mg/kg of body weight to about 200.0 mg/kg of body weight should be administered one to five times per day via any topical routes of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the antibacterially effective amount of the substantially pure glycopeptide antibiotics AC-98-3, AC-98-4 or AC-98-5 may be administered at a dosage and frequency without inducing side effects commonly experienced with conventional antibiotic therapy which could include hypersensitivity, neuromuscular blockade, vertigo, photosensitivity, discoloration of teeth, hematologic changes, gastrointestinal disturbances, ototoxicity, and renal, hepatic, or cardiac impairment. Further the frequency and duration of dosage may be monitored to substantially limit harmful effects to normal tissues caused by administration at or above the antibacterially effective amount of the substantially pure glycopeptide antibiotics AC-98-3, AC-98-4 or AC-98-5.
  • active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compound is preferred.
  • compositions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microrganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
  • a mixture of AC-98 antibiotics is prepared following the fermentation description in Example 3 of U.S. Pat. No. 3,495,004 wherein the antibiotic containing eluate is concentrated and further purified by passing through a column of deactivated silica gel followed by a weakly acidic cation exchange resin, IRC-50. Elution of the resin by acidic aqueous solution, followed by evaporation in vacuo affords a mixture of glycopeptide antibiotics AC-98.
  • the mixture of antibiotics from eleven individually isolated fermentation batches are combined to afford 23.626 g of a mixture of AC-98 antibiotics which is dissolved in 500 ml of water containing a minimum volume of butyl alcohol and filtered.
  • the filtrate is evaporated in vacuo with the further addition of butyl alcohol and continuous evaporation while removing excess water to afford a residue.
  • To the residue is added 100 ml of methyl alcohol followed by heating to the boil and centrifuging to a solid.
  • the solid is washed with methyl alcohol then acetone followed by centrifuging to afford 19.841 g of a mixture of AC-98 antibiotics as a solid after rewashing with acetone and drying.
  • the mixture of AC-98 antibiotics is analyzed by HPLC to contain mainly five components, designated as AC-98-1 (17%), AC-98-2 (19%), AC-98-3 (15%), AC-98-4 (29%), and AC-98-5 (4%).
  • the relative quantity of each antibiotic is calculated based on the integration area at 226 nm. Referring to the remaining 16% of the mixture of AC-98 antibiotics, approximately 15% belong to components which have a different UV spectra and less than 1 % further minor components of AC-98 antibiotics.
  • the analysis is performed by HPLC on a C18 column (YMC ODS-A, 5 ⁇ m particle size, 4.6 x 150 mm).
  • the mobile phase monitored by UV detector at 226 nm, is a gradient of acetonitrile (10% to 50%) in water containing 0.01 % trifluoroacetic acid over 22 minutes at a flow rate of 1 ml per minute.
  • the relative quantity of each glycopeptide antibiotic is calculated based on the integration area at 226 nm.
  • a mixture of AC-98 antibiotics(180 mg) from Example 1 is dissolved in water (1 ml) and subjected to reverse phase HPLC on a C18 column (YMC ODS-A, 8 ⁇ m particle size, 20 X 250 mm).
  • the mobile phase consisting of a gradient from 11% to 25% by volume of acetonitrile in water containing 0.02% trifluoroacetic acid over 45 minutes.
  • the flow rate of the mobile phase is maintained constant at 9 ml/minute and the effluent monitored by UV absorbance at 226 nm.
  • Individually collected fractions having the same retention times by HPLC are pooled and upon evaporation infrared, proton nuclear magnetic resonance, and carbon 13 magnetic resonance spectra recorded.
  • the mixture from Table 1 (13 mg) eluted at 43 minutes is dissolved in water (200 ⁇ l) and subjected to reverse phase HPLC on a C18 column (YMC ODS-A, 8 ⁇ m particle size, 20 x 250 mm).
  • the mobile phase is a gradient of methanol (40% to 60%) in water containing 0.02% trifluoroacetic acid over 40 minutes at a flow rate of 9 ml/minute.
  • the major peak centers at 29 minutes, as monitored by UV detector at 226 nm, and upon evaporation infrared, proton nuclear magnetic resonance and carbon 13 magnetic resonance spectra are recorded.
  • the substantially pure AC-98-5 (5 mg) is isolated as a trifluoroacetate salt.
  • the in vitro antibacterial activity of substantially pure glycopeptide antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 from Examples 2 and 3 is determined against a spectrum of bacteria by a standard agar dilution method.
  • Mueller-Hinton agar containing 5% sheep blood and two-fold decreasing concentrations of substantially pure glycopeptide antibiotics AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 from Examples 2 and 3 are poured into petri dishes.
  • the agar surfaces are inoculated with 1 to 5 X 10 4 colony forming units of bacteria by means of a Steers replicating device.
  • the in vivo antibacterial activity of substantially pure glycopeptides AC-98-1, AC-98-2, AC-98-3, AC-98-4, and AC-98-5 is established by infecting female CD-1 mice from Charles River Laboratories, weighing 20 +/- 2 g each, intraperitoneally with 6.5 X 10 5 CFU/0.5 ml of broth of Staphylococcus aureus Smith. The mice are treated intravenously, 30 minutes before infection with the indicated dose of the test compound in .2 ml of water. The results of this test are given in Table III. Table III.

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Claims (7)

  1. Composition pharmaceutique comprenant un composé
    sensiblement pur ayant pour structure
    Figure imgb0022
     ou un sel pharmaceutiquement acceptable de celui-ci, en association avec un support pharmaceutiquement acceptable.
  2. Composition pharmaceutique telle que revendiquée dans la revendication 1 et dans laquelle le composé sensiblement pur a pour structure
    Figure imgb0023
  3. Composition pharmaceutique comprenant un composé
    sensiblement pur ayant pour structure
    Figure imgb0024
     ou un sel pharmaceutiquement acceptable de celui-ci, en association avec un support pharmaceutiquement acceptable.
  4. Composition pharmaceutique telle que revendiquée dans la revendication 3 et dans laquelle le composé sensiblement pur a pour structure
    Figure imgb0025
  5. Composition pharmaceutique comprenant un composé
    sensiblement pur ayant pour structure
    Figure imgb0026
     ou un sel pharmaceutiquement acceptable de celui-ci, en association avec un support pharmaceutiquement acceptable.
  6. Composition pharmaceutique telle que revendiquée dans la revendication 5 et dans laquelle le composé sensiblement pur a pour structure
    Figure imgb0027
  7. Utilisation d'un composé sensiblement pur tel que décrit dans l'une quelconque des revendications 1 à 6 ou d'un sel pharmaceutiquement acceptable de celui-ci, ou d'une composition telle que revendiquée dans l'une quelconque des revendications 1 à 6, dans la préparation d'un médicament pour traiter des infections bactériennes chez un animal à sang chaud.
EP02739179A 2001-04-25 2002-04-25 Antibiotiques glycopeptidiques sensiblement purs ac-98-1; ac-98-2; ac-98-3; ac-98-4 et ac-98-5 Expired - Lifetime EP1399176B1 (fr)

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US28624901P 2001-04-25 2001-04-25
US286249P 2001-04-25
PCT/US2002/013073 WO2002085403A1 (fr) 2001-04-25 2002-04-25 Antibiotiques glycopeptidiques sensiblement purs ac-98-1; ac-98-2; ac-98-3; ac-98-4 et ac-98-5

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EP1399176A1 EP1399176A1 (fr) 2004-03-24
EP1399176A4 EP1399176A4 (fr) 2009-02-11
EP1399176B1 true EP1399176B1 (fr) 2010-12-01

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EP02739179A Expired - Lifetime EP1399176B1 (fr) 2001-04-25 2002-04-25 Antibiotiques glycopeptidiques sensiblement purs ac-98-1; ac-98-2; ac-98-3; ac-98-4 et ac-98-5

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EP (1) EP1399176B1 (fr)
AT (1) ATE489962T1 (fr)
CA (1) CA2444907C (fr)
DE (1) DE60238481D1 (fr)
ES (1) ES2354686T3 (fr)
MX (1) MXPA03009718A (fr)
WO (1) WO2002085403A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60237360D1 (en) * 2001-04-25 2010-09-30 Wyeth Corp Glycopeptidantibiotika
US6713448B2 (en) 2001-04-25 2004-03-30 Wyeth Holdings Corporation Substantially pure glycopeptide antibiotics AC-98-1; AC-98-2; AC-98-3; AC-98-4 and AC-98-5

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3495004A (en) * 1968-08-13 1970-02-10 American Cyanamid Co Antibiotic ac-98 and production thereof
ES2110401T3 (es) * 1989-07-18 1998-02-16 Biosearch Italia Spa Antibioticos pentapeptidicos derivados de dalbaheptidos.
JP4051421B2 (ja) * 1995-07-05 2008-02-27 サノフイ−アベンテイス・エツセ・ピー・アー 等電点電気泳動によるダルバヘプチド抗生物質の精製
CN1242052C (zh) * 1998-07-16 2006-02-15 布里斯托尔-迈尔斯斯奎布公司 诺卡氏菌的生物纯培养物

Also Published As

Publication number Publication date
DE60238481D1 (de) 2011-01-13
CA2444907A1 (fr) 2002-10-31
CA2444907C (fr) 2015-02-24
EP1399176A1 (fr) 2004-03-24
ES2354686T3 (es) 2011-03-17
MXPA03009718A (es) 2004-01-29
EP1399176A4 (fr) 2009-02-11
ATE489962T1 (de) 2010-12-15
WO2002085403A1 (fr) 2002-10-31

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